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Scientists have discovered a key protein in the toxic brain pathway that leads to fragile X tremor/ataxia syndrome (FXTAS), an inherited neurodegenerative disorder. The finding, in a Drosophila (fly) model of FXTAS, could help unravel the complex mechanisms of FXTAS and lead scientists to develop therapies to target the protein. The research will be published in the Aug. 16 issue of the journal Neuron.

Fragile X tremor/ataxia syndrome was first recognized several years ago as a neurodegenerative disease caused by a premutation in carriers of the mutated FMR1 gene, the same gene that causes fragile X syndrome--the most common inherited cause of mental retardation. Individuals with the FMR1 premutation (a less exaggerated form of the mutation) do not have retardation, but instead are at risk for developing FXTAS, usually after age 50, causing progressive problems with movement (ataxia), tremor, memory loss, loss of sensation in the lower extremities (peripheral neuropathy), and mental and behavioral changes.

Fragile X syndrome occurs when a region of the FMR1 gene repeats a particular sequence of three DNA basesCGG--causing silencing of the FMRP protein. Called a trinucleotide repeat, this CGG sequence repeats only about 6 to 55 times in normal individuals, but between 200 and 1,000 times in those with fragile X syndrome.

In those with the premutation of the FMR1 gene, CGG repeats between 60 and 100 times.

Scientists estimate the frequency of fragile X syndrome as approximately 1 in 4,000 males and 1 in 8,000 females and the frequency of the FMR1 premutation as 1 in 800 males and 1 in 260 females. Approximately 20 percent of males with the permutation develop FXTAS. Approximately 20 percent of women with the premutation have premature ovarian failure a loss of ovarian function in women younger than 40.

Lead authors of the current study are Peng Jin, PhD, assistant professor of human genetics and Stephen T. Warren, PhD, Timmie professor and chair of human genetics at Emory University School of Medicine. Dr. Warren and his colleagues led an international team that discovered the FMR1 gene in 1991, later characterized the FMRP protein, and developed diagnostic tests for fragile X syndrome.

Drs. Jin and Warren earlier discovered (Neuron, 2003) that FXTAS is caused by elongated repeats of the CGG sequence in cells' RNA the molecules that translate the genetic code from DNA into proteins. In the current Neuron paper, Dr. Jin describes his discovery that the pur alpha protein, which is necessary for neuronal function and is involved in brain synapses tied to movement, is bound by the CGG trinucleotide repeats located in the RNA of the FMR1 gene.

Drs. Jin and Warren believe that because the repeated CGG sequences bind and sequester the pur alpha protein, the protein is not available for its normal function in the parts of the brain responsible for movement. The researchers also found that the pur alpha protein bound to CGG repeats becomes part of toxic brain aggregates, called inclusions, found in patients with neurodegeneration.

"Now that we have discovered a protein that is depleted by RNA in the premutation gene, we will try to identify more specifically how depletion of this protein can cause neurodegeneration, and we can use our fly model to conduct drug screening and begin to develop therapeutic drugs that could overcome this problem," says Dr. Jin.

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